In March/April of this year, an outbreak of an influenza-like illness (ILI) caused by a novel strain of H1N1 influenza began in Mexico, and then rapidly spread to and throughout the United States. During May and early June, this novel H1N1 infection spread to multiple other countries in the Americas, Europe, Asia, the Middle East, and the Pacific basin, resulting in the World Health Organization (WHO) increasing its influenza threat rating to 6, signifying a global influenza pandemic. Although the early phase of this new pandemic has been associated with mild morbidity and low mortality, a significant numbers of patients have died in the U.S. and world-wide. The second reported death in the U.S. was a pregnant woman;an event consistent with the clinically recognized increase in morbidity and mortality for pregnant women who become infected with influenza. In a recent report from the Centers for Disease Control and Prevention (CDC), 34 pregnant women with confirmed or probable cases of H1N1 infection were encountered during the first month of the outbreak in the U.S. Among these 34 pregnant women, 11 (32%) required hospitalization, three were admitted to intensive care and one died. This CDC report also noted that among 45 deaths in the U.S. between April and June 14th, 13% (6) occurred in pregnant women. During past influenza pandemics, pregnancy has been associated with a 2 to 3 fold higher mortality risk;however, the pathophysiologic mechanisms underlying this increased pregnancy-related morbidity and mortality are currently unknown. It has been speculated that the increased maternal mortality is the result of 1) a depressed immune response to infection during pregnancy, 2) an excessive innate immune response (cytokine storm) during pregnancy, and/or 3) the increased metabolic demands of pregnancy predisposing to hypoxia and septic shock. Although reasonable speculations, there is currently no experimental evidence supporting any of these pathophysiologic events during pregnancy. The goal of this new R21 application is to utilize pregnant C57BL/6 mice infected with a lethal doses of H1N1 influenza virus (mouse-adapted PR8 strain) to begin to test the novel hypothesis that the increased maternal mortality from severe influenza infection is caused by a dysfunctional immune response resulting in an inappropriate cytokine/chemokine response leading to increased lung injury, reduced ability to clear virus, and overwhelming viral septicemia culminating in the systemic inflammatory response syndrome (SIRS), multi-organ failure and death. Testing of this hypotheses will begin with the following two Specific Aims: Aim #1: Test the hypothesis that the increased maternal mortality is mediated by an excessive viral load associated with increased pulmonary injury, profound systemic hypoxia and evidence of the systemic inflammatory response syndrome (SIRS) characterized by coagulopathy and multi-organ failure. Aim #2: Test the hypothesis that the increased pulmonary and systemic manifestations of severe influenza infection during pregnancy occur in response to a dysfunctional inflammatory cytokine and chemokine response. These experimental animal studies will begin to provide the scientific basis for the clinical care of pregnant women with severe influenza infections, hopefully in time to address the needs of the current (and future) influenza pandemics. PUBLIC HEALTH RELEVANCE: In March/April of this year, an outbreak of an influenza-like illness (ILI) caused by a novel strain of H1N1 influenza began in Mexico, and then rapidly spread to the United States and the rest of the world leading the World Health Organization (WHO) to declare a global influenza pandemic on June 11th. During the current and past influenza pandemics, pregnancy has been associated with significantly higher adverse outcomes;however, the pathophysiologic mechanisms underlying this increased pregnancy-related morbidity and mortality are currently unknown. The goal of this new R21 application is to utilize pregnant C57BL/6 mice infected with a lethal doses of H1N1 influenza virus to 1) test the hypothesis that the increased maternal mortality is mediated by an excessive viral load associated with increased pulmonary injury, profound systemic hypoxia and evidence of the systemic inflammatory response syndrome (SIRS) characterized by coagulopathy and multi-organ failure, and 2) test the hypothesis that the increased pulmonary and systemic manifestations of severe influenza infection during pregnancy occur in response to a dysfunctional inflammatory cytokine/chemokine response.